Azetidinecarboxamide derivatives for treating CNS disorders

ABSTRACT

A compound of formula (1) wherein R 1  is aryl; and R 2  is hydrogen or alkyl; pharmaceutically acceptable addition compounds thereof; and their use in therapy, particularly for the treatment and prophylaxis of CNS disorders such as anxiety and epilepsy.

This is a 371 of international application PCT/G99/00223 withinternational filing date of Jan. 22, 1999 published in English.

The present invention relates to chemical compounds useful in thetreatment of disorders of the central nervous system (CNS), such asanxiety and all forms of epilepsy, particularly in humans. The inventionalso relates to the use of such compounds, pharmaceutical preparationscontaining such compounds and to methods of preparing such compounds.

Anxiety disorders affect an estimated 73 million people world-wide. Thebenzodiazepines have provided the dominant therapy for anxiety over thepast three decades and there is no doubt that they are remarkablyeffective anxiolytics. However, chronic administration ofbenzodiazepines produces severe dependence liability, withdrawalsyndromes, and side effects (sedation, amnesia, muscle relaxation). Theonly non-benzodiazepine anxiolytic that has been launched over the pastdecade is the 5-HT receptor ligand buspirone (Buspar®). This drug hashad a remarkable commercial success despite being regarded as a weakanxiolytic (compared with the benzodiazepines) and having a long latencyto onset of therapeutic action (2-4 weeks). In addition, buspirone andall related 5-HT_(1A) partial agonists suffer from a dose-limitingside-effect profile comprising nausea, vertigo and endocrine changes.

The aetiology of anxiety disorders is not fully understood, but it isnow established that benzodiazepines act by potentiating GABAergicneurotransmission although there is strong evidence that otherneurotransmitter systems are modulated indirectly—in particular, theserotonergic and noraenergic systems. Many pharmaceutical companies haveinvested considerable resource into the development of serotonergicanxiolytics. However, it is now apparent that ligands selective for 5-HTreceptor subtypes, despite displaying anxiolytic-like activity in arestricted range of anxiety models, have, at best, very weak and/ornon-dose-related mixiolytic effects in the clinic. The 5-HT₃ receptorantagonists are now discredited as psychotropics: they have a restrictedrange of activity in functional and anxiety models; they show noconvincing anxiolytic effects in the clinic; and they are now acceptedonly as useful anti-emetics. The 5-HT_(2A) antagonists similarly areregarded as ineffective in terms of psychotropic activity. The clinicalutility of 5-HT_(1A) receptor agonists and partial agonists is severelylimited by their intrinsically weak action and by the dose-limitingside-effects (vertigo, endocrine changes, nausea) which become moreintense as the agonist efficacy of these molecules is increased. Theselective CCK_(B) receptor antagonists have displayed an unimpressivepreclinical profile similar to that of selective 5-HT ligands such asthe 5-HT₃ antagonists.

Serotonergic anxiolytics include the selective serotonin reuptakeinhibitors (SSRIs) which, in addition to displaying antidepressantproperties, are also effective in anxiety disorders such as panicdisorder and obsessive-compulsive disorder. However, as with theirantidepressant action, the major drawback with these compounds is thelong delay (6-8 weeks) in the onset of clinical improvement followingchronic administration.

A strategy in recent years towards improving the clinical profile ofclassical benzodiazepines is that of developing benzodiazepine receptorpartial agonists, according to the rationale that they would have a moreselective anxiolytic action and be less liable to induce dependence.However, this approach appears to have failed owing to the very weakanxiolytic actions of these compounds and their poor side-effectprofiles (there is either a low or non-existent ratio between anxiolyticand sedative doses).

U.S. Pat. No. 4,956,359 and EP-A-0194112 disclose 3-aryloxy and3-arylthio azetidinecarboxamides and their anti-convulsant andanti-epileptic activity. These compounds, like the benzodiazepines, havelow water solubility which leads to difficulties in formulation. Thepresence of an oxygen or sulphur atom, present as a linking atom betweenthe aryl group and the azetidine ring, is a key feature of thesecompounds since such atoms can undergo hydrogenbonding interactions withother molecules, affect molecular conformation and increase electrondensity in the aryl rings.

There remains therefore a need for novel anxiolytic and anti-epilepticagents which do not suffer the above-mentioned drawbacks.

It has now been found that the oxygen and sulphur linking atoms are notnecessary for pharmacological action. It is unexpected that compounds inwhich such atoms are absent exhibit pharmacological activity.

According to the present invention there is provided a chemical compoundof formula (1)

wherein:

R¹ is aryl; and

R² is hydrogen or alkyl;

and pharmaceutically acceptable addition compounds thereof.

Reference in the present specification to an “alkyl” group means abranched or unbranched, cyclic or acyclic, saturated or unsaturated(e.g. alkenyl or alkynyl) hydrocarbyl radical. Where cyclic or acyclicthe alkyl group is preferably C₁ to C₁₂, more preferably C₁ to C₈ (suchas methyl, ethyl, propyl, isopropyl butyl, isobutyl, tert-butyl, amyl,isoamyl, hexyl, heptyl, octyl).

Reference in the present specification to an “aryl” group means a monoor bicyclic aromatic group, such as phenyl or naphthyl.

The alkyl and aryl groups may be substituted or unsubstituted. Wheresubstituted, there will generally be 1 to 3 substituents present,preferably 1 or 2 substituents. Substituents may include:

carbon containing groups such as

alkyl

aryl, arylalkyl (e.g. substituted and unsubstituted phenyl, substitutedand unsubstituted berzyl);

halogen atoms and halogen containing groups such as

haloalkyl (e.g. trifluoromethyl);

oxygen containing groups such as

alcohols (e.g. hydroxy, hydroxyalkyl, (aryl)(hydroxy)alkyl),

ethers (e.g. alkoxy, alkoxyalkyl, aryloxyalkyl),

aldehydes (e.g. carboxaldehyde),

ketones (e.g. alkylcarbonyl, alkylcarbonylalkyl, arylcarbonyl,arylalkylcarbonyl, arylcarbonylalkyl),

acids (e.g. carboxy, carboxyalkyl),

acid derivatives such as esters

(e.g. alkoxycarbonyl, alkoxycatbonylalkyl, alkycarbonylyoxy,alkycarbonylyoxyalkyl) and amides

(e.g. aminocarbonyl, mono- or dialkylaminocarbonyl, arninocarbonylalkyl,mono- or dialkylaminocarbonylalkyl, arylaniinocarbonyl);

nitrogen containing groups such as

amines (e.g. amino, mono- or dialkylamino, aminoalkyl, mono- ordialkylaminoalkyl),

azides,

nitriles (e.g. cyano, cyanoalkyl),

nitro;

sulphur containing groups such as

thiols, thioethers, sulphoxides and sulphones

(e.g. alkylthio, alkylsulfinyl, alkylsufonyl, alkylthioalkyl,alkylsulfinylalkyl, alkylsulfonylalkyl, arylthio, arylsulfinyl,arylsulfonyl, arylthioalkyl, arysylalkyl arylsulfonylalkyl); and

heterocyclic groups containing one or more, preferably one, heteroatom,

(e.g. thienyl, fliranyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolylisothiazolyl, oxazolyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl,imidazolinyl, pyrazolidinyl, tetrahydrflranyl, pyranyl, pyronyl,pyridyl, pyrazinyl, pyridazinyl, piperidyl, piperazinyl, morpholinylthionaphthyl, benzofirayl, isobenzofuryl, indolyl, oxyindolyl,isoindolyl, indazolyl, indolinyl, 7-azaindolyl, isoindazolyl,benzopyranyl, coumarinyl, isocoumarinyl, quinolyl, isoquinolyl,naphthridinyl, cinnolinyl, quinazolinyl, pyridopyridyl, benzoxazinyl,quinoxadinyl, chromenyl, chromanyl, isochromanyl and carbolinyl).

Preferred substituents include alkyl, aryl, halo, or anhalogen-containing group such as trifluoromethyl.

As used herein, the term “alkoxy” means alkyl-O— and “alkoyl” meansalkyl-CO—.

As used herein, the term “halogen” means a fluorine, chlorine, bromineor iodine radical, preferably a fluorine or chlorine radical.

The compounds of formula (1) may exist in a number of diastereomericand/or enantiomeric forms. Reference in the present specification to “acompound of formula (1)” is a reference to all stereoisomeric forms ofthe compound and includes a reference to the unseparated stereoisomersin a mixture, racemic or non-racemic, and to each stereoisomer in itspure form.

In the compounds of formula (1), preferably R¹ is a substituted orunsubstituted aryl group selected from phenyl and naphthyl, morepreferably R¹ is a substituted phenyl or naphthyl, more preferably R¹ isphenyl or naphthyl having 1 to 3 substituents and most preferably R¹ isphenyl or naphthyl having 1 or 2 substituents. In a preferred embodimentof the invention, R¹ is a mono- or di-substituted phenyl group,preferably a mono-substituted phenyl group.

Where R¹ is napthyl, it is preferred that R¹ is 2-naphthyl.

The preferred substituent groups are selected from halo (preferablyfluoro and chloro), trifluoromethyl and tertiary butyl, and morepreferably from fluoro, chloro and trifluoromethyl.

Where R¹ is a phenyl having 1 substituent, the phenyl group ispreferably para- or meta-substituted. Where R¹ is a phenyl having 2substituents, the phenyl group is preferably 2,3-disubstituted,2,4-disubstituted, 3,4-disubstituted or 3,5-disubstituted, preferably3,4-disubstituted.

Where R¹ is disubstituted, it is preferred that R¹ is substituted by twohalo groups, the same or different, or by one halo group and onetrifluoromethyl group. More preferably, R¹ is dichloro-, difluoro-,chloro-fluoro- or fluoro-trifluoromethyl-substituted.

The R¹ groups are preferably selected from 4-chlorophenyl,4-fluorophenyl, 4-(trifluoromethyl)phenyl, 3-(trifluoromethyl)phenyl,3,4-difluorophenyl, 3,4-dichloropbenyl, 3-chloro-4-fluorophenyl,4-chloro-3-fluorophenyl, 3-fluoro-4-(trifluoromethyl)phenyl,4-fluoro-3-(trifluoromethyl)phenyl and 3-chloro-5-fluorophenyl.

In one embodiment of the present invention R² is alkyl, preferablyselected from C₁₋₈ alkyl, more preferably from alkenyl, alkynyl,hydroxyalkyl, alkoxyalkyl and unsubstituted saturated cyclic and acyclichydrocarbyl, and more preferably from propyl, 2-propenyl, 2-propynyl and2-hydroxypropyl.

Particularly preferred compounds are as follows:

Chirality R¹ R² — 4-Cl—C₆H₄ 2-propenyl — 4-F—C₆H₄ 2-propenyl — 4-F—C₆H₄2-propynyl R 4-F—C₆H₄ MeCH(OH)CH₂ — 4-Cl—C₆H₄ 2-propynyl R 4-Cl—C₆H₄MeCH(OH)CH₂ S 4-F—C₆H₄ MeCH(OH)CH₂ S 4-CF₃—C₆H₄ MeCH(OH)CH₂ — 3-CF₃—C₆H₄2-propynyl — 4-CF₃—C₆H₄ 2-propynyl R 4-CF₃—C₆H₄ MeCH(OH)CH₂ — 4-CF₃—C₆H₄H

Of these, the preferred compounds are:3-(4-Chlorophenyl)-N-(2-propynyl)azetidine-1-carboxamide,(S)-3-(4-Fluorophenyl)-N-2-hydroxypropyl)azetidine-1-carboxarnide,3-(4-Fluorophenyl)-N-(2-propynyl)azetidine-1-carboxamide,(R)-3-(4-Fluorophenyl)-N-(2-hydroxypropyl)azetidine-1-carboxanide,3-(4-Chlorophenyl)-N-2-propenyl)azetidine-1-carboxarnide,(S)-3-(4-Trifluoromethyl)phenyl)-N-(2-hydroxypropyl)azetidine-1-cawboxamide,3-(3-Trifluoromethyl)phenyl)-N-(2-propynyl)azetidine-1-carboxamide and3-(4-(Trifluoromethyl)phenyl)-N-azetidine-1-carboxamide.

According to a further aspect of the present invention there is provideda compound according to the present invention for use in therapy.

The compounds of the present invention may be used in the treatment(including prophylaxis) of CNS disorders. In particular, the compoundsof the present invention may be used in the treatment (includingprophylaxis) of anxiety, epilepsy, insomnia, including travel insomniaand insomnia associated with terminal illness, alcohol withdrawalsyndrome, chronic and acute pain, neurodegenerative diseases (forexample, senile dementia) and symptoms related to withdrawal fromsubstance abuse. The compounds may also be used in the relief ofspasticity. The compounds of the present invention may also be used inmuscle relaxation prior to surgery or surgical manipulation or aspre-medication prior to surgery.

In a preferred embodiment of the present invention, the compounds areused in the treatment (including prophylaxis) of anxiety or epilepsy.

Anxiety includes generalised anxiety disorder (GAD), panic disorder,panic disorder plus agoraphobia, simple (specific) phobias (e.g.arachnophobia, performance anxiety such as public speaking), socialphobias, post-traumatic stress disorder, anxiety associated withdepression, and obsessive compulsive disorder (OCD).

Epilepsy is a chronic disorder characterised by recurrent seizures. Twoforms of epilepsy exist—partial and generalised epilepsy—and each typeis subdivided into idiopathic (cause unknown) or symptomatic (causeknown). There are two fundamental types of seizures: partial seizureswhich includes simple partial seizures, complex partial seizures, andpartial seizures secondarily generalised; and generalised seizures whichincludes generalised tonic-clonic seizures (grand mal), absence seizures(petit mal), myoclonic seizures, atonic seizures, clonic seizures, andtonic seizures.

According to a further aspect of the present invention there is provideduse of a compound of the present invention in the manufacture of amedicament for the treatment (including prophylaxis) of CNS disorders,preferably anxiety, epilepsy, insomnia, including travel insomnia andinsomnia associated with terminal illness, alcohol withdrawal syndrome,chronic and acute pain, neurodegenerative diseases, symptoms relating towithdrawal from substance abuse or spasticity, and more preferablyanxiety or epilepsy.

According to a further aspect of the present invention there is provideduse of a compound of the present invention in the manufacture of amedicament for muscle relaxation prior to surgery or surgicalmanipulation or as pre-medication prior to surgery.

The invention further provides a method of treatment (includingprophylaxis) of CNS disorders, preferably anxiety, epilepsy, insomnia,including travel insomnia and insomnia associated with terminal illness,alcohol withdrawal syndrome, chronic and acute pain, neurodegenerativediseases, symptoms relating to withdrawal from substance abuse andspasticity, and more preferably anxiety or epilepsy, comprisingadministering to a patient in need of such treatment an effective doseof a compound according to the present invention.

The invention further provides a method of muscle relaxation prior tosurgery or surgical manipulation or as pre-medication prior to surgery,comprising administering to a patient in need thereof an effective doseof a compound according to the present invention.

According to a further aspect of the present invention there is provideda method of preparing a compound of the present invention.

Compounds of the present invention may be prepared according to thereaction scheme (where P is a nitrogen protecting group). R¹ and R² areas previously defined. The 3-aryl-3-azetidinol (III) may be formed bytreatment of the ketone (II) with an organometallic reagent such as anaryllithium or an arylmagnesium halide. Removal of the hydroxyl group togive the 3-arylazetidine (IV) may be effected by several methodsincluding, for example, catalytic hydrogenolysis; treatment with lithiumor sodium and ammonia; conversion to the xanthate by treatment withcarbon disulphide, methyl iodide and base, followed by tin-mediatedreduction; and conversion to the 3-aryl-3-chloroazetidine analogue usingan alkylsulfonyl chloride and a base, followed by a reductivedechlorination using sodium, lithium or nickel. Formation of theazetidine (V) is achieved by reaction of (IV) with a suitable nitrogendeprotection agent. For example, if P is a diphenylmethyl group, thendeprotection may be carried out by either catalytic transferhydrogenation (e.g. ammonium formate and palladium catalyst) or bytreatment with 1-chloroethyl chloroformate followed by methanol. Theurea (I) is formed by reaction of azetidine (V) with anN-alkylisocyanate or an N-alkylcarbamoyl chloride and a base such astriethylamine or potassium carbonate. Alternatively, the urea may beprepared directly from the azetidine (IV) without isolation of anintermediate such as the secondary amine (V). For example, when P is adiphenylmethyl group, azetidine (IV) may be treated with phosgenefollowed by amine R²NH₂ to give urea (I) directly.

The invention further provides a pharmaceutical composition comprising acompound according to the present invention in combination with apharmaceutically acceptable carrier or excipient and a method of makingsuch a composition comprising combining a compound according to thepresent invention with a pharmaceutically acceptable carrier orexcipient.

Compounds of the present invention may be administered in a formsuitable for oral use, for example a tablet, capsule, aqueous or oilysolution, suspension or emulsion; for topical use including transmucosaland transdermal use, for example a cream, ointment, gel, aqueous or oilsolution or suspension, salve, patch or plaster, for nasal use, for aexample a snuff, nasal spray or nasal drops; for vaginal or rectal use,for example a suppository; for administration by inhalation, for examplea finely divided powder or a liquid aerosol; for sub-lingual or buccaluse, for example a tablet or capsule; or for parenteral use (includingintravenous, subcutaneous, intramuscular, intravascular or infusion),for example a sterile aqueous or oil solution or suspension. In generalthe above compositions may be prepared in a conventional manner usingconventional excipients, using standard techniques well known to thoseskilled in the art of pharmacy. Preferably, the compound is administeredorally.

For oral administration, the compounds of the invention will generallybe provided in the form of tablets or capsules or as an aqueous solutionor suspension.

Tablets for oral use may include the active ingredient mixed withpharmaceutically acceptable excipients such as inert diluents,disintegrating agents, binding agents, lubricating agents, sweeteningagents, flavouring agents, colouring agents and preservatives. Suitableinert diluents include sodium and calcium carbonate, sodium and calciumphosphate, and lactose, while corn starch and alginic acid are suitabledisintegrating agents. Binding agents may include starch and gelatin,while the lubricating agent, if present, will generally be magnesiumstearate, stearic acid or talc. If desired, the tablets may be coatedwith a material such as glyceryl monostearate or glyceryl distearate, todelay absorption in the gastrointestinal tract.

Capsules for oral use include hard gelatin capsules in which the activeingredient is mixed with a solid diluent, and soft gelatin capsuleswherein the active ingredient is mixed with water or an oil such aspeanut oil, liquid paraffin or olive oil.

For intramuscular, intrperitoneal, subcutaneous and intravenous use, thecompounds of the invention will generally be provided in sterile aqueoussolutions or suspensions, buffered to an appropriate pH and isotonicity.Suitable aqueous vehicles include Ringer's solution and isotonic sodiumchloride. Aqueous suspensions according to the invention may includesuspending agents such as cellulose derivatives, sodium alginate,polyvinyl-pyrrolidone and gum tragacanth, and a wetting agent such aslecithin. Suitable preservatives for aqueous suspensions include ethyland n-propyl p-hydroxybenzoate.

It will be appreciated that the dosage levels used may vary over quite awide range depending upon the compound used, the severity of thesymptoms exhibited by the patient and the patient's body weight.

The invention will now be described in detail with reference to thefollowing examples. It will be appreciated that the invention isdescribed by way of example only and modification of detail may be madewithout departing from the scope of the invention.

EXPERIMENTAL Antagonism of 3-MPA-Induced Seizures

Several animal seizure models are available for the screening andcharacterisation of anticonvulsant (antiepileptic) drugs, Most modelsemploy a chemical convulsant to induce seizures and the anticonvulsantpotencies of novel compounds are measured in terms of their ability toincrease the dose of convulsant required to induce a seizure response(or to prolong the latency to seizure onset following a bolus dose ofthe convulsant). Most chemical convulsants work by blocking theneurotran nitter function of gamma-aminobutyric acid (GABA), thepredominant inhibitory neurotransmitter in the mammalian brain. This canbe achieved by blocking the postsynaptic action of GABA usingpentylenetetrazol or bicuculline, or via a presynaptic action using aGABA synthesis inhibitor to decrease GABA release into the synapse. Inthis case, the inhibitor of glutamate decarboxylase (GAD),3-mercaptopropionic acid (3-MPA), was used as the convulsant challengeagent Anticonvulsant effects of test compounds were determined by theirabilities to significantly increase the dose of 3-MPA required toinitiate a seizure response.

Male albino T/O strin mice (obtained from Tuck) weighing 28-40 g wereused in these studies. Animals were assigned randomly to treatmentgroups and vehicle or test drug (at a dose of 30 mg/kg) wereadministered p.o. to groups of 12 animals 60 min before theadministration of a bolus dose of 3-MPA intravenously. Immediatelyfollowing 3-MPA administration, each mouse was placed individually intoa cage for observation. The seizure response of each animal was scoredquantally as present or absent (response or non-response) during the 5min period immediately following 3-MPA administration. A seizureresponse was defined as the onset of the initial clonic phase of theseizure (abrupt loss of righting reflex accompanied by vocalisation).The seizure threshold (in terms of mg/kg i.v. of 3-MPA required to evokea seizure response) was determined in each treatment group by asequential up/down method followed by modified probit analysis of thequantal data. A range of doses of 3-MPA was prepared (12.5-200.0 mg/kgi.v.) increasing by a constant geometric factor (³√2), which was foundin pilot studies to generate suitable data for analysis by this method.

In these studies, 3-MPA was obtained from Sigma.

Test compounds were prepared as solutions dissolved in 45% w/v aqueous2-hydroxypropyl-β-cyclodextrin in distilled water. 3-MPA was dissolvedin isotonic saline and its pH adjusted to 6 using 1M sodium hydroxidesolution. Drugs were administered in a dose volume of 10 ml/kg bodyweight. The test results are shown in Table 1.

TABLE 1 Antagonism of 3-MPA-Induced Seizures: Results of TestingCompound SC SV Example 1 42.7 15.7 Example 2 24.2 18.6 Example 3 21.418.6 Example 4 27.3 18.6 Example 5 32.4 15.7 Example 6 59.5 20.6 Example7 54.4 20 Example 8 100 15.7 Example 9 29.7 14.9 Example 10 95.8 15.6Example 15 58.4 14.1 Example 19 >200.0^(a) 17.2 SC = Seizure thresholdafter treatment with test drug SV = Seizure threshold in vehicle-treatedgroup ^(a) = No seizures were observed at the top dose of 200 mg/Kg i.v.of 3-MPA

Measurement of Anxiolytic Activity in Mice Using the Elevated Zero-mazeModel

The elevated “zero-maze” is a modification of the elevated plus-mazemodel of anxiety which incorporates both traditional and novelethological measures in the analysis of drug effects (Shepherd, J. K.,Grewal, S. S., Fletcher, A., Bill, D. J. and Dourish, C. T.,.Behavioural and pharmacological characterisation of the elevated “maze”as an animal model of anxiety. Psychopharmacology, 1994, 116, 56-64).

Male Sprague-Dawley rats (Charles River) weighing 300-450 gm are used.Animals are group-housed (5 per cage; cage size: 40×40×20 cm) in atemperature-controlled environment (20±2° C.), under a 12 h light-darkcycle (lights on: 08:00 hours). Food and water are made freelyavailable. Four hours prior to testing, animals are transferred to cleancages and moved to the testing room in order to habituate to the testingenvironment.

The maze is comprised of a black Perspex annular platform (105 cmdiameter, 10 cm width) elevated to 65 cm above ground level, dividedequally into four quadrants. Two opposite quadrants are enclosed byclear red Perspex walls (27 cm high) on both the inner and outer edgesof the platform, while the remaining two opposite quadrants aresurrounded only by a Perspex “lip” (1 cm high) which serves as a tactileguide to animals on these open areas. To facilitate the measurement oflocomotor activity, the apparatus is divided into octants by splittingeach quadrant into equal halves using high contrast white lines Theapparatus is illuminated by dim red lighting arranged in such a manneras to provide similar lux levels in both the open and closed quadrants(40-60 lux). A video camera, connected to a VCR in an adjacentobservation room, is mounted overhead in order to record behaviour onthe maze for subsequent analysis.

Chlordiazepoxide hydrochloride [CDP; Sigma Chemical Co. Ltd., Poole],which has previously been shown to display robust anxiolytic-likeeffects in the zero-maze, serves as positive control. Drugs aretypically dissolved in a 45% solution of2-hydroxy-propyl-β-cyclodextrin, and adminstered orally by gavage 1 hourprior to zero-maze testing.

Rats are placed on a closed quadrant and a 5 min test period is recordedon video-tape. The maze is cleaned with a 5% methano/water solution anddried thoroughly between test sessions. Five behavioural parameters arescored: [1] percentage of time spent on the open areas; [2] frequency ofhead dips over the edge of the platform when subjects are located ineither the open or the end of the closed quadrants; [3] frequency ofstretch-attend postures (SAP) from closed to open quadrants, determinedwhen the subject, on a closed quadrant, exhibits an elongated bodyposture stretched forward with at least the snout passing over theopen/close divide; [4] frequency of rearing; and [5] the number of linecrossings. Animals are scored as being in the open area when all fourpaws were in an open quadrant, and in the closed area only when all fourpaws passed over the open/closed divide. All testing is carried outbetween 1100 and 1700 hours.

An increase in the frequency of head dips is considered to be a measureof anxiolytic activity. The compound of example 6 was found to beeffective at a dose of 100 mg/Kg.

CHEMISTRY 1-(Diphenylmethyl)-3-azetidinol (2)

The compound (2) was prepared according to the method of Anderson andLok (J. Org. Chem. 1972, 37, 3953, the disclosure of which isincorporated herein by reference), m.p. 111-112° C.(lit. m.p. 113° C.).

1-Diphenylmethyl-3-azetidinone (3)

Dimethyl sulfoxide (0.36 mL, 5 mmol) was added dropwise to a stirredsolution of oxalyl chloride (0.40 mL, 4.6 mmol) in dichloromethane (20mL) at −78° C. under an argon atmosphere. The mixture was stirred for 10minutes then a solution of 1-(diphenylmethyl)-3-azetidinol (1.0 g, 4.2mmol) in dichloromethane (20 mL) was added dropwise. The mixture waswarmed to −50° C. and sired for 30 minutes. Triethylamine (2.9 mL, 21mmol) was added and the mixture warmed to room temperature. After 1hour, water (50 mL) was added and the mixture extracted withdichloromethane (4×50 mL). The combined organic extracts were washed(brine), dried (Na₂SO₄) and concentrated in vacuo to give1-diphenylmethyl-3-azetidinone (3) as a pale yellow crystalline solid(1.0 g, 99%) (lit. (S. S. Chattetjee and A. Shoeb, Synthesis, 1973,153)m.p. 82° C.).

3-(4-Chlorophenyl)-1-(diphenylmethy)-3-azetidinol (4)

To a stirred solution of 4-chlorophenylmagnesium bromide (9.1 mL, 10 Min diethyl ether) in diethyl ether (80 mL) at −78° C. under an argonatmosphere was added compound 3 (1.8 g, 7.6 mmol) in diethyl ether (50mL) dropwise over 20 minutes. The reaction mixture was stirred at −78°C. for 2 hours, then slowly warmed to room temperature with stirringover 18 hours. The reaction mixture was then partitioned between aqueousammonium acetate solution (50 mL) and diethyl ether (50 mL). The aqueouslayer was extracted with diethyl ether (3×50 mL) and the combinedorganic extracts were washed (water, brine), dried (Na₂SO₄), filteredand concentrated in vacuo to give the crude product as a pale yellowviscous oil in quantitative yield. A sample purified for analysis bycolumn chromatography on silica gel using 15-30% ethyl acetate-hexane aseluent and subsequent crystallisation from bexane gave3-(4-chorophenyl)-1-(diphenyhnethyl)-3-azetidinol (4), m.p. 108° C.Found: C, 75.42; H, 5.79; N, 3.98. C₂₂H₂₀CINO requires C, 75.53; H,5.76; N, 4.00%.

O-(3-(3-(4-Chloropbenyl)-1-diphenylmethyl))azetidinyl)-S-methyldithiocarbonate(5)

To a stirred suspension of sodium hydride (0.4 g of a 60% suspension inmineral oil, 10.4 mmol) (prewashed with hexane) in THF (80 mL) was addeddropwise a solution of compound 4 (1.7 g, 4.9 mmol) in ThF (80 ml). Themixture was stirred for 3 hours then carbon disulphide (17.6 mL, 0.29mol) and methyl iodide (6.1 mL, 0.1 mol) were added dropwise. Themixture was stirred at room temperature for 15 hours and then heated to50° C. while the solvent was removed in a stream of argon. When thevolume of the mixture was reduced by half, the mixture was concentratedin vacuo to an approximate volume of 20 mL and then partitioned betweenwater and diethyl ether. The organic layer was washed with water andthen brine, dried (Na₂SO₄), filtered and concentrated in vacuo. Thecrude product was crystallised from hexane to giveO-(3-(3-(4-chlorophenyl)-1-diphenylmethyl))azetidinyl)-S-methyldithiocarbonate(5) (2.06 g, 96%).

3-(4-Chlorophenyl)-1-(dipheoylmethyl)azetidine (6)

To a stirred solution of tributyltin hydride (1.8 ml, 6.9 mmol) in drytoluene (40 mL) at reflux under an argon atmosphere was added dropwise,over 1 hour, a solution of compound 5 (2.0 g, 4.6 mmol) in toluene (40mL). The mixture was heated under reflux for a further 2 hours then wasconcentrated in vacuo. The residue obtained was purified by flash columnchromatography on silica gel using hexane and then 10% ethylacetate-hexane as eluent. The product was recrystallised twice fromhexane to give 3-(4-chlorophenyl)-1-(diphenylmethyl)azetidine (6) (0.4g, 34%) m.p. 82° C. Found: C, 78.94; H. 6.06; N, 4.14. C₂₂H₂₀CINrequires C, 79.15; H, 6.04; N, 4.20%.

3-(4-Chlorophenyl)azetidine (7)

To a solution of compound 6 (0.36 g, 1.1 mmol) in 1,2-dichloroethane (10mL) containing proton sponge (0.02 g), cooled in an ice-water bath underan argon atmosphere, was added dropwise 1-chloroethyl chloroformate (0.3mL, 3.1 mmol). The resultant solution was boiled at reflux for 4 hours,cooled and was concentrated in vacuo. The residue obtained was mixedwith methanol (10 mL) and heated under reflux for 2 hours, then cooledand concentrated in vacuo to give the hydrochloride salt of3-(4-chlorophenyl)azetidine (7) which was used without furtherpurification.

EXAMPLE 1 3-(4-Chlorophenyl)-N-2-propenyl)azetidine-1-carboxamide (8)

To the hydrochloride salt of 3-(4-chlorophenyl)azetidine (7)(approximately 1.1 mmol) in ethanol (10 mL) stirred at 0C was addedsequentially and dropwise allyl isocyanate (0.15 mL, 1.7 mmol) followedby triethylamine (0.3 mL, 2.2 mmol). After 20 minutes the reactionmixture was partitioned between aqueous ammonium chloride and ether. Theorganic layer was washed (water and then brine), dried (Na₂SO₄),filtered and concentrated in vacuo to give a crude product. The productobtained was purified by column chromatography on silica gel using 20%ethyl acetate-hexane as eluent to give3-(4-chlorophenyl)-N-2-propenyl)azetidine-1-caboxamide (8) which wasrecrystallised from cyclohexaneltoluene (0.16 g, 61%), m.p. 112° C.Found: C, 6220; H, 6.23; N, 11.40. C₁₃H₁₅CIN₂O requires C, 62.28; H,6.03;N, 11.17%.

3-(4-tert-Butylphenyl)-1-diphenylmethyl-3-azetidinol (9)

To a stirred solution of 4-tert-butylphenyhnagnesium bromide (11.5 mL,2.0M (Et₂O)) in toluene (50 mL) at −78° C. under argon, was added,dropwise, a solution of 1-diphenylmethyl-3-azetidinone (3) (5.0 g) intoluene (100 mL) over 30 minutes. The mixture was stirred for 4 hours at−78° C. then warmed to room temperature and partitioned between aqueousammonium chloride solution (50 mL) and diethyl ether (3×50 mL). Thecombined organic fractions were washed (water, brine), dried (Na₂SO₄)and concentrated in vacuo. Recrystallisation from cyclohexane gave3-(4-tert-butylphenyl)-1-diphenylmethyl-3-azetidinol (9) (6.23 g), m.p.168-169° C. (cyclohexane). Found: C. 83.68; H, 7.97; N, 3.72. C₂₆H₂₉NOrequires C, 84.06; H, 7.87; N, 3.77%.

3-(4-tert-Butylphenyl)-3-chloro-1-(diphenylmethyl)azetidine (10)

To a stirred solution of compound (9) (6.23 g) andN,Ndiisopropylethylamine (3.5 mL) in dichloromethane (100 mL) at 0° C.was added, dropwise, methanesulfonyl chloride (1.4 mL). The mixture wasstired at 0° C. for 18 hrs, then washed (water, brine), dried (Na₂SO₄)and concentrated in vacuo. The crude product was recrystallised fromhexane to give3-(4-tert-butylphenyl)-3-chloro-1-(diphenylmethyl)azetidine (10) (4.73g) m.p. 145° C. (hexane). Found: C, 80.30; H, 7.05; N, 3.64. C₂₆H₂₈CINrequires C, 80.08; H. 7.24; N, 3.59%.

3-(4-tert-Butylphenyl-1-(diphenylmethyl)azetidine (11)

To a stirred suspension of Raney Nickel (8.6 g, wet slurry) in tertiarybutanol (50 mL) and toluene (50 mL) was added a solution of3-(4-tert-butylphenyl)-3-chloro-1-(diphenylmethyl)azetidine (10) (4.73g) in toluene (10 mL). The mixture was heated to 80° C. for 6 hours,cooled to room temperature and filtered through kisselguhr. The filtratewas concentrated in vacuo and partitioned between diethyl ether (3×50mL) and aqueous potassium carbonate solution (50 mL). The combinedorganic extracts were washed (water, brine), dried (Na₂SO₄),concentrated in vacuo and purified by flash column chromatography (10%ethyl acetahexane) on silica Recrystallisation from methanol gave3-(4-tert-butylphenyl)-1-(diphenylnethyl)azetidine (11) (3.40 g), m.p.95° C. (methanol). Found: C, 87.84; H, 8.17; N, 3.92. C₂₆H₂₉N requiresC, 87.84; H, 822; N, 3.94%.

EXAMPLE 2 3-(4-tert-Butylphenyl)-N-(2-propenyl)azeddine-1-carboxamide(12)

To a stirred solution of3-(4-tert-butylphenyl)-1-(diphenylrnethyl)azetidine (11) (1.0 g) indichloromethane (10 mL) at 0° C. was added dropwise a solution of 20%phosgene in toluene (2.5 mL), The mixture was stirred for 90 minutesthen concentrated in vacuo. To the concentrate was added dichioromethane(10 mL) and to this solution at 0° C. was added, dropwise, withstirring, allylamine (0.8 mL). The mixture was stirred for 18 hrs atroom temperature, diluted with dichloromethane (30 mL), washed (water,brine), dried (Na₂SO₄), concentrated in vacuo and purified by flashcolumn chromatography (50% ethyl acetate-hexane) to give3-(4-tert-butylphenyl)-N-(2-propenyl)azetidine-1-carboxamide (12) (0.21g), m.p. 98-99° C. (diisopropyl ether). Found: C, 74.95; H, 8.97; N,10.25. C₁₇H₂₄N₂O requires C, 74.96; H, 8.88; N, 10.28%.

EXAMPLE 3 3-(4-tert-Butylphenyl)-N-(2-propynyl)azetidine-1-carboxamide(13)

To a stirred solution of3-(4-tert-butylphenyl)-1-(diphenylmethyl)azetidine (11) (0.5 g) indichloromethane (5 mL) at 0° C. was added dropwise a solution of 20%phosgene in toluene (0.8 mL) The mixture was stirred for 90 minutes thenconcentrated in vacuo. To the concentrate was added dichloromethane (5mL) and to this solution at 0° C. was added dropwise with stirringpropargylamine (0.24 mL). The mixture was stirred for 18 hrs at roomtemperature, diluted with dichloromethane (20 mL), washed (water,brine), dried (Na₂SO₄) and concentrated in vacuo. Trituration withdiethyl ether (2 mL) gave3-(4-tert-butylphenyl)-N-(2-propynyl)azetidine-1-carboxamide (13) (0.14g), m.p. 141° C. (diethyl ether). Found: C, 75.40; H, 8.19; N, 10.38.C₁₇H₂₂N₂O requires C, 75.52; H. 8.20, N, 10.36%.

EXAMPLE 4(R)-3-(4-tert-Butylphenyl)-N-(2-hydroxypropyl)azetidine-1-carboxamide(14)

To a stirred solution of3-(4-tert-butylphenyl)-1-(diphenylmethyl)azetidine (11) (0.50 g) indichloromethane (5 mL) at 0° C. was added dropwise a solution of 20%phosgene in toluene (0.8 mL). The mixture was stirred for 90 minutesthen concentrated in vacuo. To the concentrate was added dichloromethane(5 mL) and to this solution at 0° C. was added dropwise with stirring(R)-1-amino-2-propanot (0.25 mL). The mixture was stirred for 18 hrs atroom temperature, diluted with dichloromethane (20 mL), washed (water,brine), dried (Na₂SO₄) concentrated in vacuo and purified by flashcolumn chromatography (10% methanolthyl acetate) to give(R)-3-(4-tert-butylphenyl)-N-(2-hydroxypropyl)azetidine-1-carboxamide(14) (0.35 g), n.p. 96-97° C. (diisopropyl ether). Found: C, 69.59; H,8.74; N, 9.23. C₁₇H₂6N₂O requires C, 70.31; H, 9.02; N, 9.64%.

3-(4-Fuorophenyl)-1-diphenylmethyl-3-azetidinol (15)

To a stirred solution of 4-fluorophenylmagnesium bromide (7.0 mL, 1 .OM(Et₂O)) in toluene (20 mL) at −78° C. under argon, was added, dropwise,a solution of 1-diphenylmethyl-3-azetidinone (3) (1.4 g) in toluene (30mL) over 30 minutes. The mixture was stirred for 4 hours at −78° C. thenwarmed to room temperature and partitioned between aqueous ammoniumchloride solution (50 mL) and diethyl ether (3×20 mL). The combinedorganic fractions were washed (water, brine), dried (Na₂SO₄) andconcentrated in vacuo. Purification by flash column chromatography (20%ethyl acetate, hexane) gave3-(4-fluorophenyl)-1-diphenylmethyl-3-azetidinol (15) (1.82 g). To astirred solution of the free base (1.82 g) in ether (5 mL) was addeddropwise a solution of oxalic acid (0.49 g) in acetone (1 mL). Themixture was stirred for 5 minutes then filtered to give the oxalate salthemihydrate (2.23 g), m.p. 75° C. (acetone). Found: C, 66.71; H. 5.34;N, 3.04. C₂₄H₂₂FNOs.0.5H₂O requires C, 66.67; H, 5.32; N, 3.17%.

3-(4-Floorophenyl)-3-chlorol-(diphenylmethyl)zedine (16)

To a stirred solution of3-(4-fluorophenyl)-1-diphenylmethyl-3-azetidinol (15) (4.0 g) andN,N-diisopropylethylamine (3.2 mL) in dichloromethane (100 mL) at 0° C.was added, dropwise, methanesulfonyl chloride (125 mL). The mixture wasstirred at 0° C. for 18 hrs, then washed (water, brine) and dried(Na₂SO₄) and concentrated in vacuo. The crude product was recrystallisedfrom hexane to give3-(4-fluorophenyl)-3-chloro-1-(diphenylmethyl)azetidine (16) (22 g),m.p. 108-109° C. (hexane). Found: C, 75.13; H, 5.46; N, 3.93. C₂₂H₁₉CIFNC, 75.10; H, 5.44; N, 3.98%.

3(4-Fluorophenyl)-1-(diphenylmethyl)azetidine (17)

To a stirred suspension of Raney Nickel (2.0 g, wet slurry) in tertiarybutanol (10 mL) and toluene (50 mL) was added a solution of3-(4-fluorophenyl)-3-chloro-1-(diphenylrnethyl)azetidine (16) (1.9 g) intoluene (20 mL). The mixture was heated to 80° C. for 6 hours, cooledand filtered through kieselguhr. The filtrate was concentrated in vacuoand partitioned between diethyl ether (3×30 mL) and aqueous potassiumcarbonate solution (50 mL). The combined organic extracts were washed(water, brine), dried (Na₂SO₄), and concentrated in vacuo.Recrystallisation from diisopropyl ether gave3-(4-fluorophenyl)-1-(diphenylmiethyl)azetidine (17) (1.5 g), m.p.65-66° C. (diisopropyl ether). Found: C, 83.25; H1 6.35; N, 4.41.C₂₂H₂₀FN requires C, 8325; H, 6.35; N, 4.41%.

EXAMPLE 5 3-(4-Fluoropbenyl)-N-(2-propenyl)azetidine-1-carboxamide (18)

To a stirred solution of 3-(4-fluorophenyl)-N-(diphenylnethyl)azetidine(17) (0.67 g) in dichloromethane (5 mL) at 0° C. was added dropwise asolution of 20% phosgene in toluene (2.5 mL). The mixture was stirredfor 90 minutes then concentrated in vacuo. To the concentrate was addeddichloromethafe (5 mL) and to this solution at 0° C. was added,dropwise, with stirring, allylamine (0.5 mL). The mixture was stirredfor 18 hrs at room temperature, diluted with dichloromethane (20 mL),washed (water. brine), dried (Na₂SO₄) and concentrated in vacuo.Recrystallisation from diisopropyl ether gave3-(4-(fluorophenyl)-N-(2-propeny)azetidine-1-carboxamide (18) (0.30 g),m.p. 119-120° C. (diisopropyl ether). Found: C, 66.61; H, 6.37; N,11.74. C₁₃H₁₅FN₂O requires C, 66.65; H. 6.45; N, 11.95%.

EXAMPLE 6 3-(4-Fluorophenyl)-N-(2-propynyl)azetddine-1-carboxamide (19)

To a stirred solution of 3-(4fluorophenyl)-1-(diphenylmethyl)azetidine(17) (0.38 g) in dichloromethane (5 mL) at 0° C. was added dropwise asolution of 20% phosgene in toluene (1.4 mL). The mixture was stirredfor 90 minutes then concentrated in vacuo. To the concentrate was addeddichloromethane (5 mL) and to this solution at 0° C. was added,dropwise, with stirring propargylaminc (0.3 mL). The mixture was stirredfor 18 hrs at room temperature, diluted with dichworomethane (20 mL),washed (water, brine), dried (Na₂SO₄) and concentrated in vacuo. Thecrude material was purified by flash column chromatography (50% ethylacetate hexane) and then crystallised from diisopropyl ether to give3-(4-fluoropenyl)-N-(2-propynyl)azetidine-1-carboxamide (19) (0.14 g),m.p. 141° C. (diisopropyl ether). Found: C, 67.32; H, 5.65; N, 11.93.C₁₃Hi₃FN₂O requires C, 67.23; H, 5.64; N, 12.06%.

EXAMPLE 7(R)-3-(4-Fluorophenyl)-N-(2-hydroxypropyl)azetidine-1-carboxamide (20)

To a stirred solution of 3-(fluorophenyl)-1-(diphenylmethyl)azetidine(17) (0.35 g) in dichloromethane (5 mL) at 0° C. was added dropwise asolution of 20% phosgene in toluene (1.2 mL). The mixture was stirredfor 90 minutes then concentrated in vacuo. To the concentrate was addeddichloromethane (5 mL) and to this solution at 0° C. was added dropwisewith stirring (R)-1-amino-2-propanol (0.2 mL). The mixture was sired for18 hrs in at room temperature,diluted with dichloromethane (20 mL),washed (water, brine), dried (Na₂SO₄) and concentrated in vacuo. Thecrude product was purified by flash column chromatography (10%methanol-ethyl acetate) togive)-3-(R4fluorophenyl)-N-(2-hydroxypropylaetidine-1-carboxanide (20)(0.21g), m.p. 104-105° C. (toluene/ethanol). Found: C, 61.93; H, 6.97;N, 10.9. C₁₃H₁₇FN₂O₂ requires C, 61.89; H, 6.79; N, 11.10%

EXAMPLE 8 (3-(4-Chlorophenyl)-N-2-propynyl)azetidine-1-carboxamide (21)

This compound was prepared from3-(4--chlorophenyl-1-(diphenylmethyl)azetidine (6) and propargylamineusing the procedure outlined in Example 3, m.p. 160° C. (diethyl ether).Found C, 62.85; H, 5.38; N, 10.89 C₁₃H₁₃CIN₂O requires C, 62.78; H.5.27; N, 11.26%.

EXAMPLE 9(R)-3-(4-Chlorophenyl)-N-(2-hydroxypropyl)azetidine-1-carboxiamide (22)

This compound was prepared from compound (6) and (R)-1-amino-2-propanolusing the procedure outlined in Example 4, m.p. 92-93° C. (diethylether-toluene). Found: C, 58.97; H, 6.38; N, 9.96.C₁₃H₁₇CIN₂O₂.0.2PhCH₃, requires C, 60.23; H, 6.48; N, 9.76%.

EXAMPLE 10(S-3-(4-Fluoropbenyl)-N-(2-hydroxypropyl)azetidine-1-carboxamide (23)

This compound was prepared from compound (17) and (S)-1-amino-2-propanolusing the procedure described for compound (20). m.p. 102-104° C. Found:C, 61.94; H, 6.72; N, 11.1. C₁₃H₁₇FN₂O₂ requires C, 61.89, H, 6.79; N,11.10%.

3-(3,4-Dichlorophenyl)-1-(dipbenylmethyl)azetidin-3ol (24)

This compound was prepared from compound (3) and3,4-dichlorophenylmagnesium bromide using the procedure described forcompound (4).

3-(3,4-Dicblorophenyl)-3-chloro-1-(diphenylmethyl)azetidine (25)

This compound was prepared from compound (24) using the proceduredescribed for compound (10).

3-(3,4-Dichlorophenyl)-1-(diphenylmethyl)azetidine (26)

This compound was prepared from compound (25) using the proceduredescribed from compound (11).

EXAMPLE 11 3-(3,4-Dichlorophenyl)-N-(2-propynyl)azetidine carboxamide(27)

This compound was prepared from compound (26) and propargylamine usingthe procedure described for compound (12). mp. 105.5-107.5° C.

EXAMPLE 12 (R-3-(3,4-Dichlorophenyl)-N-(2-hydroxypropyI)azetidinecarboxanide (28)

This compound was prepared from compound (26) and (R)-1-amino-2-propanolusing the procedure described for compound (12). m.p. 123-125° C. Found:C, 51.58; H, 5.33; N, 9.26. C₁₃H₁₆Cl₂N₂O₂ requires C, 51.50; H. 5.32; N,9.24%.

EXAMPLE 13 (S)-3-(3,4-Dichloropbenyjy)-N-(2-hydroxypropyl)azetidinecarboxamide (29)

This compound was prepared from compound (26) and (S)-1-amino-2-propanolusing the procedure described for compound (12). m.p. 123-125° C. Found:C, 51.47; H, 5.30; N, 9.18. C₁₃H₁₆Cl₂N₂O₂ requires C, 51.50; H, 5.32; N,9.24%.

3-(4-(Trifluoromethyl)phenyl)-1-(diphenylmethyl)azetidin-3-ol (30)

This compound was prepared from compound (3) and4-(trifluoromethyl)phenylmagnesium bromide using the procedure describedfor compound (4).

3-Chloro-3-(4-(trifluoromethyl)phenyl)(dipbenylmethyl)azetidine (31)

This compound was prepared from compound (30) using the proceduredescribed for compound (10).

3-(4-(Trifluoromethyl)phenyl)-1-(diphenylmethyl)azetidine (32)

This compound was prepared from compound (31) using the proceduredescribed for compound (11).

EXAMPLE 14(R)-3-(4-(Trifluoromethyl)phenyl)-N-(2-hydroxypropyl)azetidinecarboxamide (33)

This compound was prepared from compound (32) and (R)-1-amino-2-propanolusing the procedure described for compound (12). m.p. 107-108° C. Found:C, 54.78; H, 5.75; N, 9.01. C₁₄H₁₇F₃N₂O₂.0.25 H₂O requires C, 54.81; H.5.71, N, 9.13%.

EXAMPLE 15 (S)-3-(4-Trifluoromethyl)phenyl)-N-(2-hydroxypropyl)azetidinecarboxamide (34)

This compound was prepared from compound (32) and (S)-1-amino-2-propanolusing the procedure described for compound (12). m.p. 107-108° C. Found:C, 54.75; H, 5.68; N, 9.09. C₁₄H₁₇F₃N₂O₂.0.25 H₂O requires C, 54.81; H,5.71; N, 9.13%.

EXAMPLE 163-(4-(Trifluorometbyl)phenyl)-N-(2-propynyl)azetidine-1-carboxamide (35)

This product was prepared from compound (32) and propargylamine usingthe procedure described for compound (12). m.p. 151-155° C.

3-(3-(Trifluoromethyl)phenyl)-1-(dipheoylmethyl)azetidin-3-ol (36)

This compound was prepared from compound (3) and3-(trifluoromethyl)phenylmagnesium bromide using the procedure describedfor compound (4).

3-Chloro-3-(3-(trifluoromethyl)phenyl)-(diphenylmethyl)azetidine (37)

This compound was prepared from compound (32) using the proceduredescribed for compound (10).

3-(3-(Trifluoromethyl)phenyl)-1-(diphenylmethyl)azetidine (38)

This compound was prepared compound (37) using the procedure describedfor compound (11).

EXAMPLE 17(R)-3-(3-(Trifluoromethyl)phenyl)-N-(2-hydroxypropyl)azetidinecarboxanide (39)

This compound was prepared from compound (38) and (R)-1-amino-2-propanolusing the procedure described for compound (12). mp. 81-82° C.

EXAMPLE 18(S)-3-(3-(Trifluoromethyl)phenyl)-N-(-2-hydroxypropyl)azetidiecarboxanide (40)

This compound was prepared from compound (38) and (S)-1-amino-2-propanolusing the procedure described for compound (12). m.p. 80-82° C.

EXAMPLE 193-(3-(Trifluoromethyl)phenyl)-N-(2-propynyl)azetidine-1-carboxamide (41)

This product was prepared from compound (38) and propargylamine usingthe procedure described for compound (12). m.p. 121° C.

EXAMPLE 20 3-(4-(Trilfluoromethyl)phenyl)-N-azetidine-1-carboxamide (42)

To a solution of3-(4-(Trifluoromethyl)phenyl)-1-(diphenylmethyl)azetidine (32) (8.2mmol) in dichloromethane (20 mL) at 0° C., was added a solution ofphosgene (1.75M in toluene, 10.2 mmol). The reaction mixture was stirredat room temperature for 90 minutes, concentrated in vacuo, thenredissolved in TBlF (25 mL), cooled to 0° C. and treated with ammoniumhydroxide (12.5 mL). The reaction was stirred for 16 h, then water (80mL) and ethyl acetate (100 mL) were added and the layers were separated.The aqueous layer was extracted with ethyl acetate (2×100 mL), combinedorganic layers washed with brine (60 mL), dried (Na₂SO₄) andconcentrated in vacuo. The residue was triturated using ethyl acetate(60 mL) to a solid (1.64 g, 81%), mp. 207.5-208.5−° C. (ethyl acetate).Found: C, 54.51; H, 4.59; N, 11.41. C₁₄H₁₇CIN₂O₂ requires: C, 54.10; H,4.54; N, 11.47.

EXAMPLES 21 TO 84 See Table 2

These producted were prepared using the procedure described for compound12.

TABLE 2 Example Compound No. No. Structure Formula M Wt mp C found 21 43

C13H16F2N2O2 270.28 108-109 57.79 22 44

C13H16F2N2O2 270.28 108-109 57.73 23 45

C13H16ClFN2O2 286.74 83-84 54.44 24 46

C13H16ClFN2O2 286.74 83-84 54.46 25 47

C13H12F2N2O 250.25 123.0 62.36 26 48

C13H12ClFN2O 266.70 133.0 58.56 27 49

C14H16F4N2O2 320.29 69-71 52.44 28 50

C14H12F4N2O 300.26 119.0 56.05 29 51

C14H19ClN2O2 282.77 102.0 59.69 30 52

C13H16ClFN2O2 286.74 oil 31 53

C13H12ClFN2O 266.70 132.0 58.53 32 54

C14H17F3N2O2 302.30 89.0 55.65 33 55

C14H13F3N2O 282.27 101.0 59.70 34 56

C13H17ClN2O2 268.75 109.0 57.15 35 57

C13H16Cl2N2O2 303.19 111.0 51.43 36 58

C13H16F2N2O2 270.28 88-89 57.74 37 59

C11H11F3N2O 244.22 198.0 54.14 38 60

C14H19ClN2O2 282.77 110.0 59.33 39 61

C13H17ClN2O2 268.75 71-75 40 62

C13H17ClN2O2 268.75 82-85 58.09 41 63

C14H19ClN2O2 282.77 134-135 59.31 42 64

C19H21ClN2O2 344.84 120-122 43 65

C17H18ClN3O 315.81 125.0 64.75 44 66

C16H22ClN3O 307.83 137-138 49.82 45 67

C13H17FN2O 236.29   117-118.5 66.12 46 68

C14H15F3N2O 284.28   136-137.5 59.26 47 69

C14H17F3N2O 286.30   127-128.5 58.69 48 70

C13H17FN2O2 252.29 79.5-80   61.91 49 71

C13H16Cl2N2O2 303.19 110-111 51.67 50 72

C13H16Cl2N2O2 303.19 110-111 52.00 51 73

C13H17ClN2O2 268.75 78-80 58.44 52 74

C14H15F3N2O 284.28 64-66 58.94 53 75

C13H15ClN2O 250.73 65-66 62.75 54 76

C13H15FN2O 234.28 62.5-63.5 66.52 55 77

C14H19FN2O2 266.32   77-78.5 63.25 56 78

C15H19F3N2O2 316.33 94.5-96   57.00 57 79

C12H15FN2O2 238.26  99-101 60.41 58 80

C14H16F4N2O2 320.29 106-107 52.41 59 81

C13H13ClN2O 248.71 90-105, decom. 62.67 60 82

C13H17ClN2O2 268.75   75-76.5 58.18 61 83

C13H12ClFN2O 266.70 108.5-110   58.50 62 84

C13H16ClFN2O2 286.74   79-80.5 54.61 63 85

C17H20N2O2 284.36 143-144 71.63 64 86

C15H18F4N2O2 334.32   110-111.5 53.85 65 87

C13H17FN2O2 252.29 90-93 62.09 66 88

C14H19ClN2O2 282.77   114-115.5 59.52 67 89

C10H11FN2O 194.21   205-208.5 61.74 68 90

C14H18ClFN2O2 300.76 112.5-113.5 55.86 69 91

C10H10ClFN2O 228.66   198-200.5 70 92

C13H16ClFN2O2 286.74   81-82.5 71 93

C13H17ClN2O2 268.75 92.5-94   58.23 72 94

C13H13FN2O 232.26 101.5-10.25 67.13 73 95

C10H11ClN2O 210.66 oil 74 96

C14H19FN2O 250.32 100-102 67.10 75 97

C14H19FN2O2 (0.3 H2O) 266.32 77-79 61.83 76 98

C16H21FN2O2 292.36   141-142.5 65.71 77 99

C13H17FN2O2 252.29 118-120 61.59 78 100

C13H17ClN2O3 284.75 90-92 54.93 79 101

C14H20ClN3O.HCl 318.25 183-184 52.76 80 102

C14H15F3N2O2 300.28 139.5-141   56.07 81 103

C14H19ClN2O2 282.77 oil 82 104

C14H16F3N3O2 315.30 >150 decom. 53.05 83 105

C13H17FN2O2 252.29 77.5-79   61.82 84 106

C15H19F3N2O2 316.33 123-124 57.03 Example No. H found N found C exp Hexp N exp Note 21 5.96 10.28 57.77 5.97 10.36 22 5.95 10.29 57.77 5.9710.36 23 5.65 9.74 54.46 5.62 9.77 24 5.69 9.63 54.46 5.62 9.77 25 4.8111.20 62.40 4.83 11.19 26 4.53 10.45 58.55 4.53 10.50 27 5.02 8.69 52.505.03 8.74 28 4.02 9.26 56.00 4.03 9.33 29 6.69 9.80 59.47 6.77 9.90 30 a31 4.58 10.45 58.55 4.53 10.50 32 5.64 9.20 55.63 5.67 9.26 33 4.55 9.9659.57 4.64 9.92 34 6.35 10.28 58.10 6.38 10.42 35 5.24 9.19 51.50 5.329.24 36 6.11 10.34 57.77 5.97 10.36 37 4.55 11.47 54.10 4.54 11.47 386.79 9.95 59.47 6.77 9.90 39 b 40 6.41 10.36 58.10 6.38 10.42 41 6.8610.02 59.47 6.77 9.90 42 c 43 5.74 13.27 64.66 5.74 13.30 44 6.33 10.1350.55 6.49 10.40 45 7.18 11.83 66.08 7.25 11.86 46 5.39 9.93 59.15 5.329.85 47 5.89 10.03 58.73 5.98 9.78 48 6.77 11.09 61.89 6.79 11.10 495.35 9.21 51.50 5.32 9.24 50 5.41 9.24 51.50 5.32 9.24 51 6.13 10.3958.10 6.38 10.42 52 5.32 10.15 59.15 5.32 9.85 53 5.97 11.09 62.28 6.0311.17 54 6.52 11.90 66.65 6.45 11.95 55 7.25 10.52 63.14 7.19 10.51 565.85 8.82 56.96 6.05 8.85 57 6.35 11.72 60.49 6.35 11.75 58 5.11 8.7152.50 5.03 8.74 59 5.27 11.10 62.78 5.27 11.26 60 6.38 10.32 58.10 6.3810.42 61 4.44 10.53 58.55 4.53 10.50 62 5.77 9.69 54.46 5.62 9.77 637.11 9.78 71.81 7.09 9.85 64 5.51 8.34 53.89 5.42 8.38 65 6.70 10.7861.89 6.79 11.10 66 6.88 9.62 59.47 6.77 9.91 67 5.70 14.21 61.85 5.7114.42 68 6.07 9.33 55.91 6.03 9.31 69 70 71 6.41 10.26 58.10 6.38 10.4272 5.60 12.03 67.23 5.64 12.06 73 d 74 7.64 11.05 67.18 7.65 11.19 757.30 10.39 61.74 7.28 10.29 76 7.31 9.52 65.73 7.24 9.58 77 6.89 10.9561.89 6.79 11.10 78 6.07 9.79 54.84 6.02 9.83 79 6.77 13.04 52.84 6.6513.20 80 5.05 9.27 56.00 5.03 9.32 f 81 e 82 5.18 13.24 53.33 5.11 13.32g 83 6.83 11.05 61.89 6.79 11.10 84 6.08 8.88 56.96 6.05 8.85 Footnotesfor Table 2: Footnote a: IR: 3373, 3316, 2923, 2855, 1639, 1620, 1557,1488, 1462, 1434, 1378, 1304, 1153, 815 cm⁻¹. Footnote b: IR: 3500,3429, 3346, 3274, 2925, 2854, 1614, 1556, 1466, 1420, 1407, 1052, 824,536 cm⁻¹. Footnote c: IR: 3414, 3320, 3253, 2925, 2855, 1606, 1544,1492, 1460, 1376, 1316, 1092, 822, 751, 705 cm⁻¹. Footnote d: IR: 3340,3166, 2923, 2854, 1650, 1613, 1493, 1460, 1378, 1303, 1098, 820 cm⁻¹.Footnote e: IR: 3310, 2964, 2878, 1632, 1538, 1494, 1482, 1462, 1398,1328, 1093, 1015, 823, 529 cm⁻¹. Footnote f: compound (102) was made bythe oxidation of compound (33), by methods known to those skilled in theart. Footnote g: Compound (104) was made from compound (102) by methodsknown to those skilled in the art.

What is claimed is:
 1. A compound of formula (1)

wherein R¹ is aryl substituted with halo or haloalkyl; and R² ishydrogen or alkyl wherein alkyl is defined as a branched or unbranched,cyclic or acyclic, saturated or unsaturated, substituted orunsubstituted hydrocarbyl radical; and pharmaceutically acceptableaddition compounds therefore.
 2. A compound according to claim 1,wherein R¹ is selected from substituted phenyl and substituted naphthyl.3. A compound according to claim 1 wherein R¹ has 1, 2 or 3 substituentgroups.
 4. A compound according to claim 1 wherein R¹ is substitutedwith one or more groups selected from halo and trifluoromethyl.
 5. Acompound according to claim 4 wherein said halo groups are selected fromchloro and fluoro.
 6. A compound according to claim 1 wherein R¹ is ameta- or para-substituted phenyl group.
 7. A compound according to claim1, wherein R¹ is selected from 4-chlorophenyl, 4-fluorophenyl,4-trifluoromethyl)phenyl and 3-(trifluoromethyl)phenyl.
 8. A compoundaccording to claim 1 wherein R¹ is selected from a 2,3-disubstitutedphenyl group, a 2,4-disubstituted phenyl group, a 3,4-disubstitutedphenyl group and a 3,5-disubstituted phenyl group.
 9. A compoundaccording to claim 8 wherein R¹ is substituted by two halo groups, thesame or different, or by one halo group and one trifluoromethyl group.10. A compound according to claim 9 wherein R¹ is dichloro-substituted,difluoro-substituted, chloro-fluoro-substituted orfluoro-trifluoromethyl-substituted.
 11. A compound according to claim 1wherein R¹ is selected from 3,4-dichlorophenyl, 3,4-difluorophenyl,3-chloro-4-fluorophenyl, 4-chloro-3-fluorophenyl,3-fluoro-4-(trifluoromethyl)phenyl, 4-fluoro-3trifluoromethyl)phenyl and3-chloro-5-fluorophenyl.
 12. A compound according to claim 1 wherein R²is alkyl.
 13. A compound according to claim 1 wherein R² is C₁₋₈ alkyl.14. A compound according to claim 1 wherein R² is alkenyl, alkynyl,hydroxyalkyl or alkoxyalkyl.
 15. A compound according to claim 1 whereinR² is unsubstituted saturated cyclic or acyclic hydrocarbyl.
 16. Acompound according to claim 1 wherein R² is propyl, 2-propenyl,2-propynyl or 2-hydroxypropyl.
 17. A compound according to claim 1wherein the compound is selected from 3-(4-Chlorophenyl)-N-(2-propynyl)azetidine-1-carboxamide,(S)-3-(4-Fluorophenyl)-N-(2-hydroxypropyl)azetidine-1-carboxamide,3-(4-Fluorophenyl)-N-(2-propynyl)azetidine-1-carboxamide,(R)-3-(4-Fluorophenyl)-N-(2-hydroxypropyl)azetidine-1-carboxamide,3-(4-Chlorophenyl)-N-(2-propenyl)azetidine-1-carboxamide,(R)-3-(4-Chlorophenyl)-N-(2-hydroxypropyl)azetidine-1-carboxamide,3-(4-Fluorophenyl)-N-(2-propenyl)azetidine-1-carboxamide,3-(4-(Trifluoromethyl)phenyl)-N-(2-propynyl)azetidine-1-carboxamide,(R)-3-(4-(Trifluoromethyl)phenyl)-N-(2-hydroxypropyl)azetidine-1-carboxamide,(S)-3-(4-(Trifluoromethyl)phenyl)-N-(2-hydroxypropyl)azetidine-1-carboxamide,3-(3-(Trifluoromethyl)phenyl)-N-(2-propynyl)azetidine-1-carboxamide and3-(4-(Trifluoromethyl)phenyl-N-azetidine-1-carboxamide.
 18. Apharmaceutical composition comprising a compound according to claim 1 or17 in combination with a pharmaceutically acceptable carrier orexcipient.
 19. A method of treatment of CNS disorders comprisingadministering to a patient in need of such treatment an effective doseof a compound according to claim 1 or 17, wherein said method is for thetreatment of anxiety or epilepsy.
 20. A method of muscle relaxationprior to surgery, comprising administering to a patent in need thereofan effective dose of a compound according to any one claim 1 or 17.